Friday, June 18, 2010

Obesity, Diabetes, and Cancer

With the release this week of the ACS report on Diabetes and Cancer risk, we return to the growing cancer burden caused by obesity and excess weight gain during adult years. We might approach this problem from several angles. First, which cancers are caused by obesity and second, by focusing on diabetes, we might ask does this disease give added insights to the pathway from weight gain to cancer?


Weight, weight gain, and risk of cancer

While evidence shows that adult overweight and obesity are related to risk of many cancers, the growing epidemic of obesity provides a challenge to clinical practice and the implementation of guidelines for management of weight. Historical data from the past 25 years point to obesity as a cause of approximately 14% of cancer deaths in men and up to 20% of cancer deaths in women (1). These may be conservative estimates as the US population has gained substantial weight over this time period and the prevalence of overweight and obesity has increased from 15% in 1980 to 35% in 2005 (2). It is now estimated that the total health burden of overweight and obesity exceeds that for cigarette smoking (3).

A major review of weight, physical activity, and cancer incidence by the International Agency for Research on Cancer (IARC) used obesity prevalence data from Europe and relative risks from a meta-analysis of published studies and concluded in 2002 that obesity is a cause of 11% of colon cancer; 9% of postmenopausal breast cancer; 39% of endometrial cancer; 25% of kidney cancer; and 37% of esophageal cancer (4). In addition, data from the American Cancer Society (ACS) suggested that overweight and obesity were related to mortality from liver cancer, pancreatic cancer, non-Hodgkin lymphoma, and myeloma (1). This effect on mortality reflects both excess incidence and excess mortality among those with cancer. 

Since the 2002 IARC report, substantial new evidence supports a cause and effect relation between overweight, obesity, and the onset of these cancers further increasing the burden of cancer due to obesity (5). The American Institute for Cancer Research (AICR) and World Cancer Research Fund (WCRF) reported there is convincing evidence for a relation between obesity and esophageal, pancreatic, colorectal, postmenopausal breast, endometrial and kidney cancers with probable evidence for gallbladder. In addition, they found probable evidence that abdominal fatness in particular increases risk of pancreas, endometrial and postmenopausal breast cancer. Finally, emerging evidence suggests that obesity increases risk of aggressive prostate cancer (6). Overall we estimate that overweight and obesity causes approximately 20% of all cancer. Previously Doll and Peto (7) included overnutrition (overweight) with diet causing a combined 35% of all cancer.

To conclude that a cause and effect relation exists between obesity and cancer at each cancer site scientists pursue studies of mechanism that confirm the underlying biology of this relation and provide insights to guide prevention strategies. Take for example postmenopausal breast cancer. Among postmenopausal women obesity is directly related to circulating estradiol levels (8) which themselves are directly related to breast cancer risk (9-10). When the action of estrogens is interrupted by estrogen receptor modulators in randomized controlled trials, breast cancer incidence is reduced by approximately 50% (11-12).

Just as smoking cessation leads to a reduction in risk of lung cancer adding to the evidence of a cause and effect relation, so documenting a 50% reduction in risk of breast cancer among women who lost 10kg or more after menopause and kept it off (13) adds to both our understanding of this causal relation. In addition, focusing on weight loss after menopause, a time in life when obesity clearly increases risk of breast cancer, provides important evidence on the time frame for change in cause (weight) and subsequent change in cancer incidence. This reduction in incidence of postmenopausal breast cancer will follow the decline in circulating estrogen after weight loss.

For colon cancer, growing evidence points to insulin pathways mediating the effect of BMI and risk (14). Studies of blood glucose levels and colon cancer show a direct relation between higher glucose and subsequent risk (14). Providing further biologic rationale, c-peptide (15), a marker of insulin production, also shows this positive relation and animal models using insulin injection vs. saline show significant increases in colon cancer among those injected with insulin (16). Finally, preclinical data provides additional support for the insulin-IGF hypothesis of cancer risk, as outlined in several excellently detailed recent reviews (17-18). The PI3K/Akt pathway likely compromises the downstream target of insulin and is one of the most commonly altered in epithelial tumors.(18-19) In sum, strong evidence points to hyperinsulinemia as the direct pathway from adiposity to colon cancer.


Returning to the ACS committee report the concensus committee convened by ACS and the American Diabetes Association concluded that Diabetes (primarily type 2) is associated with an increased risk of liver, pancreas, endometrium, colon/rectum, breast, and bladder cancers. Furthermore, the association between diabetes and some cancers may be due in part to shared risk factors between the 2 diseases such as aging, obesity, diet, and physical inactivity. Possible mechanisms for a causal pathway between diabetes and cancer include hyperinsulinemia, hyperglycemia, and inflammation.


Building on this summary and the extensive work by Dr Renehan and colleagues revieweing the evidence linking obesity to cancer, we present summary estimates of relative risk from the rigorous meta-analysis by Renehan (5) and the likely pathway or mechanism for a causal relation between obesity and cancer (see Table 1 and 2).

Table 1. Relative Risk of Cancer per 5 kg/m2  Increase in BMI, Males, and most likely causal mechanism
Cancer
RR
Causal mechanism
Oesophageal adenocarcinoma
1.52***

Reflux esophagitis and chronic irritation
Thyroid
1.33*
Unknown
Colon
1.24***
Insulin
Renal
1.24***
In part though hypertension
Liver
1.24
Fatty liver cirrhosis
Malignant melanoma
1.17**
?
Multiple myeloma
1.11***
Inflammatory pathways – IL6
Rectum
1.09***
?
Gallbladder
1.09
Chronic secretion-gallstones and irritation
Leukemia
1.08**
?
Pancreas
1.07
Possible insulin pathway
Non-Hodgkin lymphoma
1.06***
Inflammatory pathways – IL6
Prostate¶
1.03
?
Lung
0.76***
Smoking leads to leanness and causes lung cancer
Esophageal squamous
0.71***
Smoking leads to leanness and causes squamous esophageal cancer

Relative risk for a 5 point increase in BMI. For example, the relative risk linked to a BMI of 28 compared to a BMI of 23; or a BMI of 32 compared to 27.

***p < .0001;  **p < .01; *p < .05

¶ biased to null as this includes predominantly low grade lesions

Adapted from Renehan et al, 2008; Fig 3 (5).




Table 2. Relative Risk of Cancer with RR per 5kg/m2Increased BMI, Females,  and most likely causal mechanism
Cancer
RR
Causal mechanism
Endometrium
1.59***
Endogenous Estrogen
Gallbladder
1.59*
Chronic secretion-gallstones and irritation
Oseophageal adenocarcinoma
1.51***
Reflux esophagitis and chronic irritation
Renal
1.34***
In part through hypertension
Leukemia
1.17*
Unknown
Thyroid
1.14**
Unknown
Breast (postmenopausal)
1.12*
Endogenous estrogen
Pancreas
1.12*
Possible insulin pathway
Multiple myeloma
1.11***
Inflammatory pathways – IL6
Colon
1.09***
Insulin
Non-Hodgkin lymphoma
1.07
Inflammatory pathways – IL6
Liver
1.07
Fatty liver cirrhosis
Breast (premenopausal)
0.92**
Irregular menstrual cycles- hormones
Lung
0.8*
Smoking leads to leanness and causes lung cancer
Esophageal squamous

0.57***

Smoking leads to leanness and causes squamous esophageal cancer

Relative risk for a 5 point increase in BMI. For example, the relative risk linked to a BMI of 28 compared to a BMI of 23; or a BMI of 32 compared to 27.

***p < .0001; **p < .01; *p < .05

Adapted from Renehan et al, 2008; Fig 4 5.

Impact of obesity among cancer patients
Obesity also impacts outcomes among cancer patients. Growing evidence also points to benefits of physical activity for breast and colon cancers. Dosing of chemotherapy and radiation therapy among obese patients may also be impacted and therapy related toxicity may vary with level of obesity. These issues will be addressed in a subsequent post. 

The burden of obesity on society continues to increase and warrants closer attention by health care providers, by policy makers, and within our communities. .


References

1.            Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. Apr 24 2003;348(17):1625-1638.
2.            Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999-2000. JAMA. 2002;288(14):1723-1727.
3.            Stewart ST, Cutler DM, Rosen AB. Forecasting the effects of obesity and smoking on U.S. life expectancy. N Engl J Med. Dec 3 2009;361(23):2252-2260.
4.            International Agency for Research on Cancer. Weight Control and Physical Activity. Vol 6. Lyon: International Agency for Research on Cancer; 2002.
5.            Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. Feb 16 2008;371(9612):569-578.
6.            Freedland SJ, Platz EA. Obesity and prostate cancer: making sense out of apparently conflicting data. Epidemiol Rev. 2007;29:88-97.
7.            Doll R, Peto R. The Causes of Cancer: Quantitative Estimates of Avoidable Risks of Cancer in the United States Today. New York: Oxford University Press; 1981.
8.            Hankinson SE, Colditz GA, Hunter DJ, et al. Reproductive factors and family history of breast cancer in relation to plasma estrogen and prolactin levels in postmenopausal women in the Nurses' Health Study (United States). Cancer Causes Control. May 1995;6(3):217-224.
9.            Key TJ, Appleby PN, Reeves GK, et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst. Aug 20 2003;95(16):1218-1226.
10.          Missmer SA, Eliassen AH, Barbieri RL, Hankinson SE. Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women. J Natl Cancer Inst. Dec 15 2004;96(24):1856-1865.
11.          Fisher B, Costantino J, Wickerham D, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 1998;90:1371-1388.
12.          Martino S, Cauley JA, Barrett-Connor E, et al. Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst. Dec 1 2004;96(23):1751-1761.
13.          Eliassen AH, Colditz G, Rosner B, Willett  W, Hankinson SE. Adult weight change and risk of postmenopausal breast cancer. JAMA. 2006;296:193-201.
14.          Giovannucci E. Metabolic syndrome, hyperinsulinemia, and colon cancer: a review. Am J Clin Nutr. Sep 2007;86(3):s836-842.
15.          Wei E, Ma J, Pollak M, et al. A prospective study of C-peptide, insulin-like growth factor-I, insulin-like growth factor binding protein-1, and the risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev. 2005;14:850-855.
16.          Giovannucci E. Insulin and colon cancer. Cancer Causes Control. 1995;6:164-179.
17.          Roberts DL, Dive C, Renehan AG. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu Rev Med. 2010;61:301-316.
18.          Hursting SD, Lashinger LM, Wheatley KW, et al. Reducing the weight of cancer: mechanistic targets for breaking the obesity-carcinogenesis link. Best Pract Res Clin Endocrinol Metab. Aug 2008;22(4):659-669.
19.          Carling D. The AMP-activated protein kinase cascade--a unifying system for energy control. Trends Biochem Sci. Jan 2004;29(1):18-24.


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